2014 opioid


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2014 opioid

  1. 1. Analgesics “Opioids” Pharmacology Hiwa K. Saaed PhD Pharmacology & Toxicology College of Pharmacy University of Sulaimani Ref, Lippincott's Illustrated Reviews of Pharmacology 5th ed 2012 1
  2. 2. Analgesic Analgesic – an agent that selectively relieves pain by acting in the CNS or on peripheral pain mechanisms, without significantly altering the consciousness Pain is: acute or chronic Consequence of complex neurochemical processes Subjective: perceptive and descriptive Alleviation of pain depend on its type” • Headache, arthritic pain Rx NSAIDs • Neurogenic pain Rx TCA Amitriptyline or SSRI Fluoxetine • Severe or chronic malignant pain Rx Opiods are DOC 2
  3. 3. History / Definitions • Ancient Egypt papyrus records reported the use of opium for pain Relief • Opium– mixture of alkaloids from the poppy seed • Opiates ‐ naturally occurring alkaloids such as morphine or codeine obtained from the juice of the opium poppy • Opioid – broad term to describe all “natural or synthetic ” compounds that work at the opioid receptors and produce morphine-like effects. endogenous opioid peptide neurotransmitters endorphin, enkephalins & dynorphins Opiods act by binding to specific opioid receptors in the CNS to produce the action of endogenous peptide neurotransmitters 3
  4. 4. Opioid Classifications  Chemistry • Natural • Semisynthetic • Synthetic  OPIOID RECEPTOR •Mu(μ) •Kappa(κ) •Delta (δ) INTRINSIC ACTIVITY • • • • agonist, partial/weak agonist, antagonist Mixed agonist/antagonist 4
  5. 5. Opioid receptors Mu(μ), Kappa(κ), Delta (δ) Opioids interact with receptors on the membranes of certain cells in the CNS, on nerve terminals in the periphery on cells of the gastrointestinal tract and the anatomic regions urinary bladder. Analgesic properties are mediated: • mainly via μ receptors • and κ receptors of the dorsal horn of the spinal cord. • Enkephalins interact more selectively with the δ receptors in the periphery. 5
  6. 6. Endogenous opioid receptors Mu Analgesia (supraspinal) Miosis Respiratory depression Euphoria Physical dependence Decrease GIT motility Kappa Spinal analgesia Sedation miosis Delta analgesia (spinal & supraspinal)  release of growth hormone Affective behavior Present in limbic system Sigma# Dysphora Hallucination (both visual & auditory) Respiratory and vasomotor stimulation mydriasis #“less specific” bind with non opioid agent e.g hallucinogen 6
  7. 7. Mechanism of Action All are G-protein coupled receptors and inhibit adenylate cyclase. They are also involved in • postsynaptic hyperpolarization (increasing K+ efflux) • or reducing presynaptic Ca++ influx; thus inhibits neuronal activity. 7
  8. 8. Receptor distribution High densities of opioid receptors on peripheral nerve fibers, immune cells and five general areas of the CNS: 1. Brainstem: respiration, cough, nausea & vomiting, BP, papillary diameter and stomach secretion. 2. Medial thalamus: mediating poorly localized deep pain 3. Spinal cord: in the substantia gelatinosa are involved in the receipt & integration on sensory input leading to the attenuation of painful afferent stimuli. 8
  9. 9. Receptor distribution 4. Hypothalamus: neuroendocrine secretion. 5. Limbic system: the greatest concentration in the amygdale, a major role in emotional behavior & response and little analgesic effect. 6. Periphery: they inhibit Ca+2 dependent release of excitatory, pro-inflammatory substances (substance P) 7. Immune cells: undetermined. 9
  10. 10. Opioids Strong • Alfentanil • Fentanyl • Heroin • Meperidine • Methadone • Morphine • Oxycodone • Remifentanil • Sufentanil Moderate/low • Codeine • Propoxyphene • Other • Tramadol Mixed ag/antag & partial ag • Buprenorphine • Butorphanol • Nalbuphine • Pentazocine Antagonists • Nalmefene • Naloxone • naltrexone 10
  11. 11. Opioid Agonists • The strongest naturally occurring analgesic drugs are found in opium from the poppy flower, • morphine and less potent codeine. • These drugs show a high affinity for the μ receptor and less affinity for the κ and δ receptors.
  12. 12. Morphine • Exert its effects through interaction with central & peripheral opioid receptors, binding results in hyperpolarization, inhibition of nerve firing and presynaptic inhibition of transmitter release • Acts at the κ receptors in lamina I & II of the substantia gelatinosa of the cord and decreases the release of substance P, • it also inhibits the release of excitatory transmitters from nociceptive nerve terminals centrally and in the cord 12
  13. 13. Morphine‐Pharmacological ActionsAnalgesia: Opioids cause pain relief by both • raising the pain threshold at the spinal cord level • altering the central perception of pain; awareness of pain remains but it loses its unpleasant character Euphoria: • Opioids produce a sense of contentment and well being, this may be related to stimulation of the ventral tegmental tract Respiration: • Opioids cause respiratory depression by decreasing the sensitivity of central respiratory neurons to CO2 • Occurs at therapeutic doses and as dose increases respiratory arrest will occur 13
  14. 14. Morphine‐Pharmacological Actio nsSuppression of cough reflex: • Antitussive properties do not correlate with analgesic or respiratory depression effects; this appears mediated via a different receptor complex Miosis: • Results from stimulation of μ and κ receptors located in the Edinger‐Westphal nucleus of CN III, • resistant to tolerance, 14
  15. 15. Morphine ‐ Pharmacological ActionsEmesis: • Opioids directly stimulate the chemoreceptor trigger zone in the area postrema that causes vomiting GI tract: • Opioids relieve diarrhea by decreasing gut motility and increasing the tone of intestinal smooth muscle • Constipation is also resistant to tolerance • Biliary spasm is exacerbated by increasing biliary tone with sphincter of Oddi spasm Cardiovascular: • At large doses morphine produces hypotension & bradycardia 15
  16. 16. Morphine ‐Pharmacological ActionsHistamine release: • Morphine causes mast cell degranulation, the release of histamine causing urticaria, itching, diaphoresis and vasodilation • In asthmatics it may precipitate bronchospasm Hormonal Actions:o • inhibits the release of GnRH, CRH • and deceases the release of LH, FSH & ACTH and β‐endorphin • Decrease levels f Testosterone and cortisol • Increase Prolactin and GH release via suppression of dopamine levels centrally • Increase ADH release 16
  17. 17. Morphine ‐ Therapeutic Uses ‐ • Analgesia: • Few drugs are as effective as morphine for the relief of pain • Treatment of Diarrhea • Anti‐tussive: • codeine and dextromethorphanare congeners with greater antitussive effects • Acute Pulmonary Edema: • – IV morphine dramatically relieves the dyspnea associated with pulmonary edema due to LV failure 17
  18. 18. Morphine ‐ Pharmacokinetics ‐ • Administration: • Morphine is poorly absorbed orally; codeine is a much more effective oral analgesic • Both undergo extensive first pass metabolism in the liver. Inhalation is an effective route but has found favor only with non‐medicinal administration • Implantable morphine pumps are also now use for chronic pain • Distribution: • Morphine readily enters all body tissues except the brain; morphine is the least lipid soluble of the opiates (fentanyl, methadone and heroin all enter the CNS much more quickly) 18
  19. 19. Morphine ‐ Pharmacokinetics ‐ • Metabolism: • • • • • • Conjugated in the liver, morphine–6‐glucuronide is a much more potent analgesic; however morphine‐3‐glucuronide is less analgesic Both are excreted in the urine with small amounts excreted in the bile Hepatic & renal dysfunction both prolong the normal 4‐6 hour duration of action when administered systemically to morphine-naive individuals • but considerably longer when injected epidurally, because its low lipophilicity prevents redistribution from the epidural space. 19
  20. 20. Morphine ‐ Pharmacokinetics ‐ • Note: A patient's age can influence the response to morphine. • Elderly patients are more sensitive to the analgesic effects of the drug, possibly due to decreased metabolism or other factors, such as decreased lean body mass, renal function, etc. They should be treated with lower doses. • Neonates should not receive morphine because of their low conjugating capacity. 20
  21. 21. Morphine ‐ Adverse Effects ‐ • Severe respiratory depression (μ, δ and κ receptors) • Constipation (variable, μ and κ receptors) • Nausea and vomiting • Pupillary constriction (μ/κ receptors) • Caution must be exercised when opiates are used in those with liver or renal failure • Allergy enhanced hypotensive effects • Elevation of intracranial pressure particularly head injury • Enhance cerebral and spinal ischemia 21
  22. 22. Morphine ‐ Adverse Effects ‐ • In BPH, morphine cause acute urinary retension • Patients with adrenal insufficiency or myxedema may experience extended and increased effects from the opioids. Morphine should be used with cautiously in patients with bronchial asthma or liver failure. • Note: Many of the effects above can be inhibited by opioid receptor antagonists such as naloxone. • Rapid development of tolerance • Physical dependence and abstinence syndrome 22
  23. 23. Morphine ‐Tolerance & Physical Depe ndence‐ • Repeated use produces tolerance to the effects of respiratory depression, analgesia, euphoria and sedation • Tolerance does not develop to miosis and constipation • Physical & psychological dependence readily occurs • Withdrawal induces a syndrome associated with autonomic, motor and psychological responses that are incapacitating, rarely are these life threatening 23
  24. 24. Opioid withdrawal syndrome 24
  25. 25. comparison of the maximum Efficacy versus Addiction / Abuse Potential of Various Opioids • Detoxification of heroin- or morphinedependent individuals is usually accomplished through the oral administration of • methadone, • buprenorphine, or • clonidine. 25
  26. 26. Drug interactions: • The depressant actions of morphine are enhanced by phenothiazines, MAOIs, and TCAs. • The analgesia inexplicably enhanced by Low doses of amphetamine and hydroxyzine. 26
  27. 27. Meperidine “Pethidine” (μ,…κ) • A synthetic opioid structurally unrelated to morphine • Mechanism: • It binds to μ receptors with some binding at κ receptors • Actions: • Causes respiratory depression similar to morphine, but less urine retention • no significant CV effect when given orally. • IV administration produces a decrease in PVR resulting in increased peripheral blood flow & HR. • pupillary dilation via an atropine –like effect. 27
  28. 28. Meperidine • Therapeutic uses: • • • • Severe acute pain Lacks antitussive activity No anti diarrhea; Obstetrics; Produces less smooth muscle contraction/ spasm than morphine • Pharmacokinetics: • Well absorbed form the GI tract; it is most often given IM • Shorter duration of action than morphine (2‐4 hours) • Demethylated to normeperidine in the liver and excreted in the urine NB. Because of shorter action and different route of metabolism, meperidine is preferred over morphine during labor 28
  29. 29. Meperidine-Adverse effects: With large repeated doses normeperidine (demethylated meperidine) accumulates causing • anxiety, muscle tremors and convulsions • Causes papillary dilation (vs. miosis with morphine) in large doses • Hyperactive reflexes • Severe hypotension when admin. postop. • +neuroleptics: enhanced depression • +MAOI: severe reactions convulsion & hyperthermia • Cross‐tolerance with other opioids 29
  30. 30. Methadone (μ) • This is a synthetic orally effective opioid that • is equipotent to morphine • but induces less euphoria • has a longer duration of action • Mechanism of action: • Binds to the μ receptor. • Actions: • An equipotent analgesic to morphine • Causes miosis, respiratory depression, biliary spasm and constipation just like morphine. 30
  31. 31. Methadone • Therapeutic uses: • Used for controlled withdrawal from heroin & morphine • Self addictive but the withdrawal syndrome is somewhat milder but more protracted than with other opioids • Pharmacokinetics: • Readily absorbed orally, t1/2 24hrs • Highly protein bound so remains in tissues for a prolonged period. • Transformed in the liver and excreted by the urine as mostly inactive metabolites • Adverse effects: • Similar to morphine particularly the risk of addiction 31
  32. 32. Fentanyl • Chemically related to meperidine but miosis • has 100 times the analgesic potency of morphine; used in anesthesia and as analgesia postop & during labor • Highly lipophilic: elimination half‐life is longer than morphine’s as redistribution occurs • Rapid onset of action and a short duration (15‐30 minutes) • Can be used IV, epidurally or intrathecally. Transmucosal and transdermal preparations are available • Metabolized to an inactive metabolite by the cytochrome P4503A4 system. Drug metabolites are eliminated through the urine. 32
  33. 33. Fentanyl • Like morphine fentanyl causes miosis (vs. mydriasis) • Particular risk of the transmucosal or transdermal routes is respiratory depression; these delivery routes create a reservoir of drug in the skin or mucosa. Hence, the onset is delayed 12 hours, and the offset is prolonged • Fentanyl is often used during cardiac surgery because of its negligible effects on myocardial contractility. • Muscular rigidity, primarily of the abdomen and chest wall, is often observed with fentanyl use in anesthesia. 33
  34. 34. Fentanyl derivative • Adverse effects of fentanyl are similar to those of other µ-receptor agonists. • Because of life-threatening hypoventilation, the fentanyl patch is contraindicated in the management of acute and postoperative pain or pain that can be ameliorated with other analgesics. • Sufentanil, Alfentanil & Remifentanil are related to fentanyl they differ in their potency and metabolic disposition. • Only Sufentanil is even more potent than fentanyl others are less potent 34
  35. 35. Heroin • Heroin is produced by the diacetylation of morphine which results in a three fold increase in its potency • Acetylation allows it to cross the BBB much more rapidly yielding a more pronounced euphoria • May be used IV or smoked, both allow for rapid distribution, • heroin is metabolized to morphine • No medical indication for its use in the clinic. 35
  36. 36. oxycodone • is a semisynthetic derivative of morphine. • It is orally active and is sometimes formulated with aspirin or acetaminophen. • It is used to treat moderate to severe pain and has many properties in common with morphine. • Oxycodone is metabolized to products with lower analgesic activity. • Excretion is via the kidney. • Abuse of the sustained-release preparation (ingestion of crushed tablets) has been implicated in many deaths. • It is important that the higher-dosage forms of the latter preparation be used only by patients who are tolerant to opioids. 36
  37. 37. Moderate/Weak Agonists • Codeine • Converted to morphine thus: • Much less analgesic than morphine • Less euphoria and has much lower abuse potential and rarely produces physical dependence • An effective oral analgesic • Does possess significant anti‐tussive effects at sub‐analgesic doses • Often formulated with either acetaminophen, aspirin of ibuprofen; care but be exerted when these are used with over the counter analgesic to avoid overdose with the non‐opioid agent • A synthetic congener of codeine dextromethorphan lacks analgesic properties is an effective anti‐tussive available without prescription 37
  38. 38. Moderate/Weak Agonists • Propoxyphene • Derivative of methadone, • dextro isomer is analgesic, levo isomer is antitussive • Used for mild to moderate pain; its opioid dose equipotency is about half of codeine (require twice dose) • Often formulated with another over‐the‐counter analgesic; combination has greater effect than either drug alone • Toxic doses may produce cardio and pulmonary toxicity particularly when taken in combination with alcohol and/or sedatives in addition to CNS depression • Opioid antagonists can reverse the pulmonary and CNS effects but not the cardiotoxicity 38
  39. 39. Mixed Agonists‐Antagonists & Partial Agonists • Pentazocine • Buprenorphine • Butorphanol • Nalbuphine • • • • Drugs that stimulate one receptor but block another Effects of these drugs depend on previous exposure to opioids Naïve patients – drugs act as agonists; produce pain relief Opioid dependent patients – drugs show blocking affects; withdrawal syndrome occurs 39
  40. 40. Pentazocine • Pentazocine acts as an agonist on k receptors and is a weak antagonist at µ and delta receptors. • Pentazocine promotes analgesia by activating receptors in the spinal cord, and it is used to relieve moderate pain. • It may be administered either orally or parenterally. • Pentazocine produces less euphoria compared to morphine. • In higher doses, the drug causes respiratory depression and decreases the activity of the gastrointestinal tract. • High doses increase blood pressure and can cause hallucinations, nightmares, dysphoria, tachycardia, and dizziness. The latter properties have led to its decreased use. 40
  41. 41. Pentazocine • In angina, pentazocine increases the mean aortic pressure and pulmonary arterial pressure and, thus, increases the work of the heart. • The drug decreases renal plasma flow. • Despite its antagonist action, pentazocine does not antagonize the respiratory depression of morphine, • but it can precipitate a withdrawal syndrome in a morphine abuser. Tolerance and dependence develop on repeated use. 41
  42. 42. Mixed Agonists‐Antagonists & Partial Agonists • Buprenorphine • A partial agonist at μ receptors producing morphine‐like effects in naïve users but precipitating withdrawal in morphine dependents • Metabolized in the liver and excreted in the urine and bile • May be taken sublingually or parenteral and possess a long duration of action • Adverse effects respiratory depression not reversible by naloxone, hypotension and nausea 42
  43. 43. Buprenorphine • Main use is in opioid detoxification as its withdrawal syndrome appears less severe and of shorter duration than methadone • Available outside of the specialized clinic allowed to dispense methadone for opiate withdrawal 43
  44. 44. Antagonists • Bind with high affinity to the μ, κ & δ receptors but fail to activate the receptor • In normal individuals, these agents produce no effect but in those with opiates present, they induce an acute withdrawal syndrome • Naloxone • Reverses the coma and respiratory depression associated with opioid overdose • IV administration produces a reversal of respiratory depression within ~30 seconds • Binding affinity is 10X greater at the μ receptor than κ • Relatively short T1/2 (60‐100 minutes) so reversal will often abate requiring repeat administration 44
  45. 45. Antagonists Naltrexone (hepatotoxic) • Similar actions as naloxone but an oral agent with a much longer duration of action • Single dose able to antagonize the effects of heroin for up to 48 hours Nalmefene • is a parenteral opioid antagonist with actions similar to that of naloxone and naltrexone. • It can be administered IV, intramuscularly, or subcutaneously. • Its half-life of 8 to10 hours is significantly longer than that of naloxone and several opioid agonists. 45